Optically active compounds, method for kinetic optical resolution of carboxylic acid derivatives and catalysts therefor

ABSTRACT

The present invention provides a method of kinetic optical resolution of carboxylic acid derivatives using specific optically active catalysts. A racemic or diastereomeric mixture of carboxylic acid derivatives of the formula (A) is reacted with a nucleophile in the presence of an optically active catalyst to form an optically active nucleophile derivative of the formula (B). The catalyst is an optically active compound represented by the formula (C) or (D) [wherein R 1  is a substituted or unsubstituted, saturated or unsaturated, straight-chain, branched or alicyclic aliphatic hydrocarbon group which can have a heteroatom, R 2  is ethyl or vinyl, and R 5  is hydrogen or methoxy respectively].

TECHNICAL FIELD

The present invention relates to a method of kinetic optical resolutionof carboxylic acid derivatives derived from carboxylic acids such asamino acids, more particularly to a method of kinetic optical resolutionwherein carboxylic acid derivatives derived from racemic ordiastereomeric mixtures of chiral carboxylic acid compounds are reactedwith nucleophiles in the presence of optically active catalysts toobtain optically active substances. The present invention also relatesto the catalysts to be used for the above-mentioned method of opticalresolution and further to novel optically active compounds which areuseful as, for example, the above-mentioned catalysts.

BACKGROUND ART

The demand for optically active compounds has grown rapidly in recentyears, and particularly demand for pharmaceutical intermediates in thepharmaceutical industry is increasing. Accordingly, a method ofobtaining optically active compounds efficiently is intensively studied.One method of obtaining optically active compounds is an opticalresolution method. Preferential crystallization, diastereomerresolution, kinetic resolution and the like are known as the opticalresolution methods. Since the preferential crystallization has a narrowscope of application, obtainable compounds are remarkably limited. Thediastereomer resolution requires a stoichiometric resolving agent andmulti stages, and its operation is troublesome. On the other hand, thekinetic resolution method is a technique for performing opticalresolution characterized by utilizing differences in reaction ratebetween racemates and enantiomers caused by performing reactions usingoptically active catalysts, thereby reacting only a specific enantiomerpreferentially. The kinetic resolution using enzymes mainly comes inpractice and is an effective method for obtaining optically active aminoacids, alcohols and the like. However, since the kinetic resolution withenzymes generally requires long time for the reactions, andconcentrations of substrates must be diluted in order to obtain highoptical yields, this method is unsuitable for obtaining large amounts ofoptically active compounds.

Some studies of kinetic optical resolution by chemical techniques havebeen reported. For example, as a chemical method of optically resolvingcarboxylic acid derivatives such as amino acids, an optical resolutionby alcoholysis of urethane-protected amino acid-N-carboxy anhydrides(UNCA) using cinchona alkaloid derivatives as catalysts was reportedrecently (Deng, L. et al. J. Am. Chem. Soc., 2001, 123, 12696-12697).This report states that quinidine, which is cinchona alkaloid, iseffective as a catalyst in these reactions, and use of (DHQD)₂AQN andDHQD-PHN, which are quinidine derivatives having alcohol moietyprotected with an aryl group, leads to more efficient opticalresolution. However, since (DHQD)₂AQN and DHQD-PHN are difficult tosynthesize, very expensive and hardly available, they are unsuitable foroptical resolution in large amounts. It is necessary to use quinidine,which is readily available and inexpensive, in order to perform opticalresolution in large amounts, but use of quinidine causes issues inrecycling of the catalyst, namely, quinidine itself is reacted with UNCAto give by-products, which lowers purity of the recovered catalyst.Using (DHQD)₂AQN and quinidine as catalysts, optical resolution in highsubstrate concentrations causes the problem that enantiomer selectivityis lowered. Accordingly, development of new catalysts which are readilyavailable and stable and have high optical resolution ability isdesired.

DISCLOSURE OF THE INVENTION

Studying precisely kinetic resolution by a chemical technique in view ofthe above-mentioned points, the present inventors found that kineticoptical resolution of carboxylic acid derivatives can be performedefficiently by using specific optically active catalysts, and completethe present invention.

The present invention relates to a method of a kinetic opticalresolution of a carboxylic acid derivative, wherein a racemic ordiastereomeric mixture of chiral carboxylic acid derivatives representedby the following general formula (A),

[wherein X is NR′, an oxygen atom or a sulfur atom, Y is an oxygen atomor a sulfur atom, Z is NR′, an oxygen atom or a sulfur atom, plural Rs,the same or different, are substituted or unsubstituted, saturated orunsaturated, straight-chain, branched or alicyclic aliphatic hydrocarbongroups which can have a heteroatom, substituted or unsubstitutedaromatic hydrocarbon groups, substituted or unsubstituted heterocyclicgroups, or noncarbon substituents or atoms, and n is an integer of 1 or2, when n is 1, two Rs are not the same, and when n is 2, two Rs are notthe same at at least one of adjacent two carbon atoms to which Rs arelinked, and R′ in X and Z has the same meaning as that of theabove-mentioned R or is acyl, sulfonyl, oxycarbonyl or aminocarbonyl.],is reacted with a nucleophile (Nu-H) in a solvent in the presence of anoptically active catalyst, thereby obtaining a nucleophile derivativewhich is rich in one enantiomer or diastereomer represented by thefollowing general formula (B),

[wherein Nu is OR, NR₂ or SR, and Y, Z, R, n and R in Nu have the samemeanings as those mentioned above.]an unreacted carboxylic acid derivative which is rich in the otherenantiomer or diastereomer, or both of them, characterized in that thecatalyst is an optically active compounds represented by the followinggeneral formula (C) or (D)

[wherein R¹ is a substituted or unsubstituted, saturated or unsaturated,straight-chain, branched or alicyclic aliphatic hydrocarbon group whichcan have a heteroatom, R² is ethyl or vinyl, and R⁵ is hydrogen ormethoxy.].

The carboxylic acid derivative (A) to be used as a substrate, theoptically active catalyst (C or D) and the nucleophile (Nu-H), which areimportant constituent elements of the present invention, are describedin detail below.

The carboxylic acid derivative (A) is a cyclic compound (for example, acyclic carbonate and a carbamate) derived from the racemic ordiastereomeric mixture of the chiral carboxylic acid compounds, havingat least one electrophilic reaction moiety to be attacked by thenucleophile in the presence of the catalyst and having at least oneasymmetric carbon atom.

In the carboxylic acid derivatives represented by the general formula(A), when n is 1, two Rs are not the same, and when n is 2, two Rs arenot the same at at least one of the adjacent two carbon atoms to whichtwo Rs are linked. Namely, these Rs are selected respectively such thatat least one of the carbon atoms to which two Rs are linked isasymmetric carbon.

In the present specification and claims, the saturated or unsaturatedaliphatic hydrocarbon groups can be saturated aliphatic hydrocarbongroup, namely, alkyl such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl or pentyl, or aliphatic hydrocarbon groups having acarbon-carbon unsaturated group(s) such as a carbon-carbon double bondor a carbon-carbon triple bond, namely, alkenyl such as vinyl, allyl,isopropenyl, butenyl, isobutenyl or pentenyl, or alkynyl such asethynyl, propynyl, butynyl or pentynyl.

In the present specification and claims, examples of substituents of thealiphatic hydrocarbon groups are groups and atoms generally known inorganic chemistry such as halogen, hydroxy, alkoxy, carbonyl,acyl(alkanoyl and arylcarbonyl)alkoxy, ester (alkoxycarbonyl,aryloxycarbonyl and acyloxy), phosphoryl, phosphine, phosphonate, amine,amide, imine, thiol, thioether, thioester, sulfonyl, sulfate, sulfonate,nitrile, nitro, azo, azide, hydrazide, silyl and organic metals. Thealkyl on the substituents of the aliphatic hydrocarbon groups canfurther have substituent(s). The aliphatic hydrocarbon groups can begroups having aromatic hydrocarbon group(s) such as aralkyl (forexample, benzyl and phenethyl), aralkenyl or aralkynyl, or groups havingheterocyclic group(s) such as pyridylmethyl.

In the present specification and claims, the expression “can have aheteroatom” means that at least one carbon atom(s) of the hydrocarbongroup is replaced with heteroatom(s) such as nitrogen, oxygen, sulfur,phosphorus or selenium, or that heteroatom(s) is linked through a singlebond or a multiple bond to at least one carbon atom of the hydrocarbongroups. Examples of the former are hydrocarbon groups (alkyl, aralkyl,alkylene, aralkylene and the like) having ether linkage, thioetherlinkage, —NH— linkage, sulfonyl linkage or the like. Examples of thelatter are hydrocarbon groups having carbonyl, thiocarbonyl, ester,aldehyde, nitrile or the like.

A carbon number of the aliphatic hydrocarbon groups as R is preferablyone to 30, more preferably one to 20. A member number of the alicyclichydrocarbon groups is preferably three to ten, more preferably five toseven.

The aromatic hydrocarbon groups as R (including also aromatichydrocarbon groups such as aralkyl, aralkenyl and aralkynyl) aremonocyclic aromatic hydrocarbon groups having a member number of threeto eight or polycyclic aromatic hydrocarbon groups formed by condensingtwo or more monocyclic aromatic hydrocarbon groups. Examples thereof arephenyl, naphthyl, phenancyl and anthranyl. Examples of substituents ofthe aromatic hydrocarbon groups can be the same as the above-mentionedsubstituents of the aliphatic hydrocarbon groups. The substitutedaromatic hydrocarbon groups can be phenyl having alkyl, for example,tolyl or aromatic hydrocarbon groups substituted by a transition metalsuch as Fe (Fe can have organic group(s)), for example, a ferrocene ringgroup.

The heterocyclic groups as R can be not only aromatic but alsononaromatic so far as the groups have heteroatom(s) in their ring. Theheteroatom(s) in the heterocyclic groups can be nitrogen, oxygen,sulfur, phosphorus, selenium or the like. The heterocyclic groups canhave carbonyl in their ring.

Examples of aromatic heterocyclic groups are furyl, thienyl, imidazolyl,oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazolyl.Examples of nonaromatic heterocyclic groups are so-called aliphaticheterocyclic compounds such as pyrrolidinyl, piperazinyl,tetrahydrofuryl, dihydrofuryl, 1,3-dithianyl, lactone and lactam.Examples of substituents of the heterocyclic groups are substituentsexemplified as the substituents of the aliphatic hydrocarbon groups.

In the present specification and claims, the noncarbon substituents as Rin the general formula (A) are groups containing at least one atom otherthan carbon (for example, a heteroatom such as nitrogen, oxygen, sulfur,phosphorus or selenium) and linked through this atom to carbon atom(s)of the five-membered ring or the six-membered ring of the generalformula (A). Examples of substituents are hydroxy, alkoxy, phosphoryl,phosphine, phosphonate, amine, amide, imine, thiol, thioether,thioester, sulfonyl, sulfate, sulfonate, nitro, azo, azide, hydrazide,silyl, boron-containing groups and organic metal groups. The noncarbonatoms as R in the general formula (A) are monovalent atoms linked tocarbon of the five-membered ring or the six-membered ring of the generalformula (A) and are exemplified by a hydrogen atom and a halogen atom.

Examples of R′ in X and Z are protecting groups of amino and amidedescribed in the literature (Greene, T. W. et al. Protective groups inorganic synthesis 2nd ed., United States, John Wiley & Sons, Inc., 1991,309-405) such as acyl having one to 20 carbon atoms such as formyl,acetyl, propionyl or butyryl, sulfonyl such as mesyl or tosyl,oxycarbonyl such as benzyloxycarbonyl, tert-butyloxycarbonyl orallyloxycarbonyl, and aminocarbonyl such as phenylaminocarbonyl.

Typical examples of substrates; the racemates (A-1 to A-3) and thediastereomeric mixtures (A-4 and A-5); are represented by structuralformulae below.

The catalysts to be used in the present invention are optically activeamines represented by the general formula (C) or (D).

In the formulae (C) and (D), R¹ is a substituted or unsubstituted,saturated or unsaturated, straight-chain, branched or alicyclicaliphatic hydrocarbon group which can have a heteroatom, R² is ethyl orvinyl, and R⁵ is hydrogen or methoxy group.

The substituted or unsubstituted, saturated or unsaturated,straight-chain, branched or alicyclic aliphatic hydrocarbon groups whichcan have a heteroatom as R¹ can have the same meaning as that describedabove about R of the general formula (A). The aliphatic hydrocarbongroups particularly can be alkyl such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl or pentyl, or aliphatic hydrocarbongroups having a carbon-carbon unsaturated bond such as a carbon-carbondouble bond or a carbon-carbon triple bond, namely, alkenyl such asvinyl, allyl, isopropenyl, butenyl, isobutenyl or pentenyl, or alkynylsuch as ethynyl, propynyl, butynyl or pentynyl.

Examples of substituents of aliphatic hydrocarbon groups are groups andatoms generally known in organic chemistry such as halogen, hydroxy,alkoxy, carbonyl, acyl(alkanoly and arylcarbonyl)alkoxy, ester(alkoxycarbonyl, aryloxycarbonyl and acyloxy), phosphoryl, phosphine,phosphonate, amine, amide, imine, thiol, thioether, thioester, sulfonyl,sulfate, sulfonate, nitrile, nitro, azo, azide, hydrazide, silyl andorganic metals. The alkyl on the substituents of the aliphatichydrocarbon groups can further have substituent(s). The aliphatichydrocarbon groups can be groups having aromatic hydrocarbon group(s)such as aralkyl (for example, benzyl and phenethyl), aralkenyl oraralkynyl, or groups having heterocyclic group(s) such as pyridylmethyl.

Preferred optically active compounds are compounds wherein R¹ is asubstituted or unsubstituted, saturated or unsaturated, straight-chain,branched, alicyclic aliphatic hydrocarbon group having one to 20 carbonatoms, R² is ethyl or vinyl, and R⁵ is hydrogen or methoxy in the abovegeneral formula (C) or (D).

Other preferred optically active compounds are compounds wherein R¹ is agroup represented by the following general formula (G), (H), (J) or (K)

[wherein R⁴, R⁶, R⁷, R⁸, R⁹ and R¹⁰, the same or different, aresubstituted or unsubstituted, saturated or unsaturated, straight-chain,branched or alicyclic aliphatic hydrocarbon groups which can haveheteroatom(s), substituted or unsubstituted aromatic hydrocarbon groups,substituted or unsubstituted heterocyclic groups, or noncarbonsubstituents or atoms.],R² is ethyl or vinyl, and R⁵ is hydrogen or methoxy in the generalformula (C) or (D).

The noncarbon substituents or atoms as R⁴, R⁶, R⁷, R⁸, R⁹ and R¹⁰ canhave the same meanings as those described above about R of the generalformula (A).

In the compounds of the general formula (C) or (D), compounds having thegroup of the general formula (G), (H), (J) or (K) as R¹, namely,compounds wherein R¹ has a methylene chain (—CH₂—) at the terminal ofbond to O are easy to synthesize and tend to exhibit good enantiomerselectivity in optical resolution reactions. When R¹ contains anunsaturated bond or heteroatom(s), good enantiomer selectivity tends tobe obtained, too.

Further other preferred optically active compounds are compounds whereinR¹ is methyl, ethyl, propyl, isopropyl, butyl, benzyl, allyl, propynyl,tert-butoxycarbonylmethyl, 2-methoxyethyl, 2-butynyl, iso-propoxycarbonylmethyl, methoxycarbonylmethyl, o-methoxybenzyl,m-methoxybenzyl, p-methoxybenzyl, o-chlorobenzyl, m-chlorobenzyl,p-chlorobenzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl,1-naphthylmethyl, 2-naphthylmethyl, prenyl, cinnamyl, methallyl,homoallyl, homobenzyl, aminocarbonylmethyl,N,N-diethylaminocarbonylmethyl, cyanomethyl, acetylmethyl,cyclopropylmethyl, 3-phenyl-2-propynyl, 3-methoxycarbonyl-2-propynyl or3-methoxycarbonyl-2-propenyl, R² is ethyl or vinyl, and R⁵ is hydrogenor methoxy in the formula (C) or (D).

R¹ in the above general formula (C) can be substituted alkyl representedby the following general formula (E), or R¹ in the above general formula(D) can be substituted alkyl represented by the following generalformula (F).

[wherein R² and R⁵ have the same meanings as those defined about theformula (C). R³ is a substituted or unsubstituted, saturated orunsaturated, straight-chain, branched or alicyclic divalent aliphatichydrocarbon group which can have heteroatom(s).]

The divalent aliphatic hydrocarbon groups can be alkylene, alkylenehaving vinylene, groups having an aromatic hydrocarbon group such asaralkylene, divalent groups (-aliphatic hydrocarbon group-aromatichydrocarbon group-aliphatic hydrocarbon group-), for example,(-alkylene-arylene-alkylene-), or groups having a heterocyclic group(-aliphatic hydrocarbon group-heterocyclic group-aliphatic hydrocarbongroup).

Further other preferred optically active compounds are compounds whereinR³ is ethylene, propylene, butylene, 2-butynylene, 2-butenylene,o-xylylene, m-xylylene, p-xylylene, 2,5-furylbismethylene,3,4-furylbismethylene, 2,5-thienylbismethylene, 3,4-thienylbismethylene,2,6-pyridylbismethylene, 3,5-pyridylbismethylene,2,3-pyrazylbismethylene, 2,5-pyrazylbismethylene,2,6-pyrazylbismethylene, 3,6-pyridazylbismethylene,4,5-pyridazylbismethylene, 2-oxopropylene or 2,3-dioxobutylene in theformula (E) or (F).

In the general formula (C) and (D), dihydro compounds (R² is ethyl) ofquinidine and quinine (R⁵ is methoxy) exhibit reactivity and selectivitywhich are approximately equal to those of corresponding unsaturatedcompounds (R² is vinyl) of quinidine and quinine, but the unsaturatedcompounds are preferred to the dihydro compounds in terms ofavailability.

The optically active compounds represented by the general formulae (C)and (D) can be prepared, for example, by alkylating an alcohol moiety ofcorresponding quinine or quinidine or derivatives thereof with anelectrophilic reagent such as an alkyl halide (so-called Williamsonsynthetic method) or the like. Solvents to be used are not particularlylimited. Bipolar aprotic solvents such as DMF are preferable. Theoptically active compounds represented by the general formulae (C) and(D) thus obtained can also be further converted into the other opticallyactive compounds represented by the general formulae (C) and (D). Forexample, O-propynyl can be converted into O-2-oxopropyl by hydration.

The above-mentioned optically active catalysts can also be supported onpolymers or solids through a covalent bond formed at R¹ and/or R² in thegeneral formulae (C) and (D) and insolubilized for use (Kobayashi et al.Tetrahedron Lett., 1980, 21, 2167-2170). The insolubilized catalysts canbe easily recovered by filtration after reactions.

The amount of the catalyst to be used in the present invention ispreferably 0.001 to 1,000 mol %, more preferably 0.01 to 500 mol %,further preferably 0.1 to 300 mol % to the substrate. When the amount istoo small, enantiomer selectivity and a reaction rate is lowered. Whenthe amount is too large, the catalyst is difficult to dissolve in thesolvent. The catalysts can be easily extracted and separated with acidicaqueous solutions after reactions and can be recycled.

The nucleophiles (Nu-H) to be used in the present invention can bechemical species having reactive electron pairs and can be any ofelectrically neutral species, organic anions and inorganic anions.Examples of nucleophiles are nitrogen-containing nucleophiles (amines,amides, imides, ammonia, hydrazine, azides and the like),oxygen-containing nucleophiles (water, alcohols, a hydroxide ion,alkoxydes, siloxanes, carboxylates, peroxides and the like),sulfur-containing nucleophiles (mercaptanes, thiolates, bisulfites,thiocyanates and the like), carbon-containing nucleophiles (cyanides,malonates, acetylides, enolates, inolates, Grignard reagents,organocopper reagents, organozinc reagents, organolithium reagents andthe like) and hydride anions. Amines, water, alcohols and thiols arepreferable among them. Alcohols are the most preferable since it is easyto handle. In particular, primary alcohols are preferable from thestandpoint of the reaction rate. Preferred alcohols are methanol,ethanol, n-propanol, n-butanol, benzyl alcohol, allyl alcohol,trifluoroethanol, cinnamyl alcohol and the like. Incorporating anucleophile site into the substrate, kinetic resolution by anintramolecular reaction can be performed.

The amount of the nucleophile to be used in the present invention ispreferably 10 to 1,000 mol %, more preferably 25 to 500 mol %, furtherpreferably 40 to 200 mol % to the substrate. When the amount of thenucleophile is too small, optical purities of the one optically activenucleophile derivative (B) and the other optically active unreactedcarboxylic acid derivative are sometimes insufficient. When the amountis too large, enantiomer selectivity tends to be lowered.

In the method of kinetic resolution in the present invention, when asubstrate concentration is increased, the unit yield of the opticallyactive substance increases, but the enantiomer selectivity is lowered.On the other hand, when the substrate concentration is lowered, theenantiomer selectivity is improved, but the unit yield of the opticallyactive substance is lowered. The substrate concentration to performoptical resolution is preferably 0.0001 to 5.0 mol/l, more preferably0.001 to 3.0 mol/l, further preferably 0.01 to 1.0 mol/l.

In the present invention, the addition order of the carboxylic acidderivative (A) as the substrate, the optically active catalyst (C and D)and the nucleophile (Nu-H) is not particularly limited so far as kineticresolution is performed in a mixed solution using a means such asstirring, shaking or an ultrasonic wave. In general, a method whereinthe nucleophile is added to the mixed solution of the substrate and thecatalyst gives good results in terms of the enantiomer selectivity.

In the method of kinetic resolution in the present invention, generallythe higher a reaction temperature, the shorter can be reaction time, butthe enantiomer selectivity tends to be lowered. On the other hand, whenthe reaction temperature is low, the reaction time tends to become long,and the enantiomer selectivity tends to improve. Accordingly, though thereaction temperature changes depending on the combination of thesubstrate, the catalyst and the like to be used, the temperature ispreferably −100° to 100° C., more preferably −90° to 70° C., furtherpreferably −80° to 50° C.

It is preferable to perform the method of kinetic resolution in thepresent invention in the solvent. Preferred solvents are inert solventswhich is not reacted with the substrates and the catalysts, and reactionliquids can be any of homogenous systems (the substrates and thecatalysts are dissolved in the solvent) and heterogenous systems (atleast a portion of the substrates and/or catalysts is insoluble). Thehomogenous systems are excellent in reaction rates. Examples of solventsare ether solvents (diethyl ether, dibutyl ether, 1,2-dimethoxyethane,diglyme, tert-butyl methyl ether (MTBE), tetrahydrofuran (THF), dioxane,cyclopropyl methyl ether and the like), halogenated hydrocarbon solvents(carbon tetrachloride, chloroform, dichloromethane, dichloroethane andthe like), hydrocarbon solvents (hexane, pentane and the like), aromaticsolvents (benzene, toluene, xylene, ethylbenzene, styrene, anisole,N,N-dimethylaniline, chlorobenzene, dichlorobenzene, methyl benzoate andthe like), ester solvents (ethyl acetate and the like), ketone solvents(acetone, methyl ethyl ketone and the like) and aprotic polar solvents(acetonitrile, N,N-dimethylformamide, dimethylsulfoxide and the like).These are used solely or in combination. Among them, solvents having lowpolarity such as ether solvents and aromatic solvents are preferablesince these solvents tend to exhibit high enantiomer selectivity.Solvents such as alcohols and amines which reacts with the substratescan also be used, if the solvents themselves work as the nucleophiles,or the reaction rates of the solvents with the substrates aresufficiently low. When the nucleophile is water or the hydroxide ion,solvents containing a proper amount of water or the hydroxide ion canalso be used.

The aromatic solvents are preferable since the solvents tend to preventthe enantiomer selectivity from lowering even if the substrateconcentration is increased. The aromatic solvent can be used incombination with other one or two or more solvents.

In the method of kinetic resolution in the present invention, ionicliquids, supercritical fluids and the like can also be used as solvents.Biphasic solvents such as emulsions and suspensions and lipid biphasescan also be used as solvents. Further, the reaction can also beperformed in a solid phase.

The method of kinetic resolution in the present invention can also beperformed under an atmosphere of gases which are reactive with thenucleophiles such as an HCN gas. Partial pressure of this gas ispreferably 0.1 to 1,000 atm, more preferably 0.5 to 100 atm, furtherpreferably 1 to 10 atm.

The present invention also relates to novel optically active compoundsrepresented by the above general formula (C) or (D). Definitions of thesymbols in the formula (C) or (D) are as mentioned above. Theseoptically active compounds are useful, for example, as the catalysts tobe used for the above-mentioned method of optical resolution.

The recemic or diastereomeric mixture (A) of the chiral carboxylic acidderivatives as the substrate is reacted with the nucleophile (Nu-H) inthe presence of the optically active catalyst, thereby obtaining thenucleophile derivative which is rich in one enantiomer or diastereomer,unreacted carboxylic acid derivative which is rich in the otherenantiomer or diastereomer, or both of them. In the kinetic opticalresolution, when a racemization rate of the other optically activeunreacted carboxylic acid derivative is far higher than a formationreaction rate of the nucleophile derivative (B) which is rich in oneenantiomer or diastereomer by the above-mentioned nucleophile, theformation reaction of the above-mentioned nucleophile derivative (B)which is rich in one enantiomer or diastereomer can be made proceed atthe same time as racemization of the other optically active unreactedcarboxylic acid derivative. In this case, only one optically activenucleophile derivative (B) can be formed in high optical purity and in atheoretical yield of 100% (so-called dynamic kinetic resolution; Noyori,R. et al. Bull. Chem. Soc. Jpn., 1995, 68, 36-55).

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described by giving Examples below, but thepresent invention is not limited to these Examples.

Reactor and the Like

A reactor was flame-dried under a nitrogen atmosphere, and a substrate,a nucleophile, a catalyst, a solvent and the like were introduced intothe reactor. MS4A (molecular sieve, 4A (powder): purchased from AldrichCo., Ltd. in U.S.) was used which had been flame-dried under reducedpressure immediately before use.

Solvents

Diethyl ether, MTBE (tert-butyl methyl ether), THF (tetrahydrofuran) andtoluene were used which had been distilled using benzophenone ketylimmediately before use.

Nucleophiles

Methanol (MeOH), ethanol (EtOH), allyl alcohol (CH₂═CHCH₂OH) andtrifluoroethanol (CF₃CH₂OH) were used which had been distilled underdrying with CaH₂.

Synthesis of Raw Materials

Phenylalanine, 4-chlorophenylalanine and 2-thienylalanine, which areα-racemic amino acids, were purchased from BACHEM Co., Ltd. inSwitzerland. 2-Aminooctanoic acid, which is an α-racemic amino acid, and3-aminobutanoic acid, which is a β-racemic amino acid, were purchasedfrom Aldrich Co., Ltd. in U.S. 3-Phenyllactic acid and mandelic acid,which are α-racemic hydroxycarboxylic acids, were purchased from FLUKACo., Ltd. in Switzerland. Five-membered ring derivatives (substrates(1)a, (1)b, (1)c and (1)d) derived from a -racemic amino acids weresynthesized according to the literatures (Daly, W. H. et al.,Tetrahedron Lett., 1988, 29, 5859-5862 and Fuller, W. D. et al.,Biopolymers, 1996, 40, 183-205). A six-membered ring carboxylic acidderivative(N-tert-butyloxycarbonyl-4-methyl-4,5-dihydro-1,3-oxazin-2,6-dione(substrate (4)) derived from β-racemic amino acid was synthesizedaccording to the literature (Mckiernan, M. et al., J. Org. Chem., 2001,66, 6541-6544). 1,3-Dioxolane-2,4-dione derivatives (substrates (7)a and(7)b) derived from α-hydroxycarboxylic acids were synthesized accordingto the literature (Toyooka, K. et al., Heterocycles, 1989, 29, 975-978).

Structural formulae of the carboxylic acid derivatives as substrates areas follows.

Catalysts

Quinidine, quinine, dihydroquinine, cinchonidine and (DHQD)₂AQN werepurchased from Aldrich Co., Ltd. in U.S. These compounds were convertedinto the following Me-Q, Me-QD, Bn-Q, CH₂═CHCH₂-Q, Et-Q, HC≡CCH₂-Q,t-BuO₂CCH₂-Q, MeOCH₂CH₂-Q, HC CCH₂—HQ, HC≡CCH₂—CD, MeC≡CCH₂-Q,i-PrO₂CCH₂-Q, o-MeOC₆H₄CH₂-Q, o-ClC₆H₄CH₂-Q, 2-PyCH₂-Q, 2-FurCH₂-Q,2-ThCH₂-Q, Me₂C═CHCH₂-Q, H₂NCOCH₂-Q, Et₂NCOCH₂-Q, NCCH₂-Q,cyclo-C₃H₅CH₂-Q, PhC≡CCH₂-Q, MeCOCH₂-Q, o-Q-CH₂C₆H₄CH₂-Q, Q-(CH₂)₄-Q,Q-CH₂C≡CCH₂-Q and HC≡CCH₂-QD, which are O-alkyl ether derivatives, touse them in Examples.

In Comparative Examples, quinidine, quinine, dihydroquinine andcinchonidine, whose alcohol moieties are free, and (DHQD)₂AQN, whosealcohol moiety is protected with aryl, were used.

All chemical purities of the catalysts before optical resolutionreactions were 99% or higher according to ¹H NMR analysis.

In the above-mentioned symbols of the catalysts, QD, Q, DHQ and CD meanquinidine, quinine, dihydroquinine and cinchonidine respectively(Kacprzak, K. et al., Synthesis, 2001, 961-998).

Examples of synthesis of O-alkyl ether derivatives are shown below.Other O-alkyl ether derivatives can be synthesized in a same manner asthese Examples.

Synthesis of O-methylquinine (Me-Q)

NaH (0.52 g, 13 mmol, purity in mineral oil: 60%) was washed with hexaneat room temperature under a nitrogen atmosphere, and then DMF (50 ml)was added to the NaH to give a suspension. Quinine (3.24 g, 11 mmol) wasadded to the suspension little by little, and the reaction mixture wasstirred for two hours until it becomes a yellow transparent solution,followed by cooling to 0° C. Methyl iodide (1.42 g, 10 mmol) was addedslowly to the solution, then the temperature of the reaction mixture wasraised to room temperature, followed by stirring the mixture for onehour. The reaction mixture was cooled to 0° C. again, water (50 ml) waspoured into the reaction mixture carefully, and toluene (50 ml) wasadded thereto. The aqueous and the organic layers were separated. Theorganic layer was washed with toluene (15 ml×3), and the organic layercombined with this toluene was washed with water (20 ml×5) and driedover anhydrous Na₂SO₄. The solvent was evaporated under reducedpressure, and the residue was purified by flash column chromatography(hexane:acetone:diethylamine=25:25:1) to give colorless viscous liquidO-methylquinine (1.62 g, yield: 44%). Chemical purity of Me-Q measuredby ¹H NMR analysis was 99% or higher.

¹H NMR (CDCl₃) δ: 1.45-1.60 (m, 1H), 1.70-1.80 (m, 4H), 2.20-2.30 (m,1H), 2.55-2.80 (m, 2H), 3.05-3.15 (m, 2H), 3.31 (s, 3H), 3.35-3.45 (m,1H), 3.94 (s, 3H), 4.85-5.00 (m, 3H), 5.65-5.80 (m, 1H), 7.31 (d, J=2.7Hz, 1H), 7.37 (dd, J=9.2, 2.7 Hz, 1H), 7.41 (d, J=4.6 Hz, 1H), 8.04 (d,J=9.2 Hz, 1H), 8.76 (d, J=4.3 Hz, 1H).

Synthesis of O-methylquinidine (Me-QD)

Colorless viscous liquid O-methylquinidine was synthesized (1.76 g,yield: 52%) in the same manner as that of the synthesis of Me-Q exceptthat quinine was changed to quinidine. Chemical purity of Me-QD measuredby ¹H NMR analysis was 99% or higher.

¹H NMR (CDCl₃) δ: 1.10-1.25 (m, 1H), 1.40-1.60 (m, 2H), 1.70-1.80 (m,1H), 2.00-2.35 (m, 2H), 2.70-3.05 (m, 4H), 3.25-3.35 (m, 1H), 3.32 (s,3H), 3.93(s, 3H), 5.05-5.12 (m, 3H), 6.02-6.15 (m, 1H), 7.29 (d, J=2.7Hz, 1H), 7.37 (dd, J=9.2, 3.0 Hz, 1H), 7.42 (d, J=4.3 Hz, 1H), 8.04 (d,J=9.2 Hz, 1H), 8.75 (d, J=4.6 Hz, 1H).

Synthesis of O-benzylquinine (Bn-Q)

Colorless viscous liquid O-benzylquinine was synthesized (2.69 g, yield:65%) in the same manner as that of synthesis of Me-Q except that methyliodide was changed to benzyl chloride. Chemical purity of Bn-Q measuredby ¹H NMR analysis was 99% or higher.

¹H NMR (CDCl₃) δ: 1.40-1.90 (m, 5H), 2.15-2.32 (m, 1H), 2.50-2.70 (m,2H), 3.00-3.20 (m, 2H), 3.30-3.50 (m, 1H), 3.91 (s, 3H), 4.37-4.48 (m,2H), 4.88-5.20 (m, 2H), 5.20 (d, J=1.5 Hz, 1H), 5.67-5.83 (m, 1H),7.28-7.41 (m, 7H), 7.47 (d, J=4.6 Hz, 1H), 8.06 (d, J=9.2 Hz, 1H), 8.76(d, J=4.3 Hz, 1H).

Synthesis of O-allylquinine (CH₂═CHCH₂-Q)

Colorless viscous liquid O-allylquinine was synthesized (2.84 g, yield:78%) in the same manner as that of the synthesis of Me-Q except thatmethyl iodide was changed to allyl chloride. Chemical purity ofCH₂═CHCH₂-Q measured by ¹H NMR analysis was 99% or higher.

¹H NMR (CDCl₃) δ: 1.45-1.65 (m, 2H), 1.70-1.87 (m, 3H), 2.19-2.35 (m,1H), 2.55-2.73 (m, 2H), 3.06-3.20 (m, 2H), 3.35-3.53 (m, 1H), 3.80-4.02(m, 2H), 3.93 (s, 3H), 4.88-4.98 (m, 2H), 5.13-5.34 (m, 3H), 5.67-5.80(m, 1H), 5.88-6.02 (m, 1H), 7.31 (d, J=2.3 Hz, 1H), 7.37 (dd, J=9.2, 2.6Hz, 1H), 7.44 (d, J=4.3 Hz, 1H), 8.04 (d, J=9.2 Hz, 1H), 8.75 (d, J=4.3Hz, 1H).

Synthesis of O-ethylquinine (Et-Q)

Colorless viscous liquid O-ethylquinine was synthesized (2.04 g, yield:58%) in the same manner as that of the synthesis of Me-Q except thatmethyl iodide was changed to ethyl bromide. Chemical purity of Et-Qmeasured by ¹H NMR was 99% or higher.

¹H NMR (CDCl₃) δ: 1.24 (t, J=6.8 Hz, 3H), 1.45-1.60 (m, 2H), 1.70-1.90(m, 3H), 2.20-2.34 (m, 1H), 2.55-2.80 (2H), 3.05-3.16 (m, 2H), 3.36-3.52(m, 3H), 3.93 (s, 3H), 4.86-4.97 (m, 2H), 5.06 (d, J=3.6 Hz, 1H),5.66-5.79. (m, 1H), 7.31 (d, J=2.3 Hz, 1H), 7.37 (dd, J=9.1, 2.8 Hz,1H), 7.44 (d, J=4.3 Hz, 1H), 8.03 (d, J=9.1 Hz, 1H), 8.74 (d, J=4.3 Hz,1H).

Synthesis of O-propylquinine (CH≡CCH₂-Q)

Colorless viscous liquid O-propylquinine was synthesized (2.47 g, yield:62%) in the same manner as that of the synthesis of Me-Q except thatmethyl iodide was changed to propynyl bromide. Chemical purity ofCH≡CCH₂-Q measured by ¹H NMR analysis was 99% or higher.

¹H NMR (CDCl₃) δ: 1.42-1.82 (m, 5H), 2.20-2.33 (m, 1H), 2.46 (t, J=2.4Hz, 1H), 2.56-2.72 (m, 2H), 3.04-3.24 (m, 2H), 3.35-3.50 (m, 1H),3.87-3.95 (m, 1H), 3.94 (s, 3H), 4.22 (dd, J=15.9, 2.4 Hz, 1H),4.89-4.99 (m, 2H), 5.33 (d, J=4.3 Hz, 1H), 5.69-5.82 (m, 1H), 7.36-7.43(m, 3H), 8.04 (d, J=9.7 Hz, 1H), 8.76 (d, J=4.6 Hz, 1H).

Synthesis of O-(tert-butoxycarbonylmethyl)quinine (t-BuO₂CCH₂-Q)

Colorless viscous liquid O-(tert-butoxycarbonylmethyl)quinine wassynthesized (2.36 g, yield: 49%) in the same manner as that of thesynthesis of Me-Q except that methyl iodide was changed to tert-butylchloroacetate. Chemical purity of t-BuO₂CCH₂-Q measured by ¹H NMR was99% or higher.

¹H NMR (CDCl₃) δ: 1.40-1.95 (m, 4H), 1.44 (s, 9H), 2.20-2.32 (m, 2H),2.55-2.80 (m, 2H), 3.03-3.23 (m, 2H), 3.45-3.60 (m, 1H), 3.75 (d, J=16.2Hz, 1H), 3.94 (s, 3H), 3.96 (d, J=16.2 Hz, 1H), 4.90-4.99 (m, 2H),5.21-5.35 (brs, 1H), 5.69-5.82 (m, 1H), 7.30-7.47 (m, 3H), 8.04 (d,J=9.5 Hz, 1H), 8.75 (d, J=4.6 Hz, 1H).

Synthesis of O-(2-methoxyethyl)quinine (MeOCH₂CH₂-Q)

Colorless viscous liquid O-(2-methoxyethyl)quinine was synthesized (2.14g, yield: 51%) in the same manner as that of the synthesis of Me-Qexcept that methyl iodide was changed to 2-methoxyethyl chloride.Chemical purity of MeOCH₂CH₂-Q measured by ¹H NMR analysis was 99% orhigher.

¹H NMR (CDCl₃) δ: 1.45-1.85 (m, 4H), 2.05-2.33 (m, 2H), 2.55-2.75 (m,2H), 3.06-3.14 (m, 2H), 3.32-3.60 (m, 5H), 3.36 (s, 3H), 3.94 (s, 3H),4.87-4.98 (m, 2H), 5.13 (d, J=3.2 Hz, 1H), 5.67-5.79 (m, 1H), 7.33 (brs,1H), 7.37 (dd, J=8.9, 2.7 Hz, 1H), 7.47 (d, J=4.6 Hz, 1H), 8.03 (d,J=9.2 Hz, 1H), 8.75 (d, J=4.6 Hz, 1H).

Synthesis of O-propynyldihydroquinine (CH≡CCH₂-DHQ)

Colorless viscous liquid O-propynyldihydroquinine was synthesized (2.84g, yield: 71%) in the same manner as that of the synthesis of Me-Qexcept that methyl iodide and quinine were changed to propynyl bromideand dihydroquinine. Chemical purity of CH≡CCH₂-DHQ measured by ¹H NMRanalysis was 99% or higher.

¹H NMR (CDCl₃) δ: 1.42-2.00 (m, 10H), 2.30-2.35 (m, 2H), 2.46 (t, J=2.4Hz, 1H), 3.04-3.24 (m, 2H), 3.35-3.50 (m, 2H), 3.87-3.95 (m, 1H), 3.96(s, 3H), 4.22 (dd, J=15.6, 2.4 Hz, 1H), 5.69-5.82 (m, 1H), 7.36-7.43 (m,3H), 8.04 (d, J=9.7 Hz, 1H), 8.76 (d, J=4.6 Hz, 1H).

Synthesis of O-propynylcinchonidine (CH≡CCH₂—CD)

Colorless viscous liquid O-propynylcinchonidine was synthesized (2.56 g,yield: 70%) in the same manner as that of the synthesis of Me-Q exceptthat methyl iodide and quinine were changed to propynyl bromide andcinchonidine. Chemical purity of CH≡CCH₂—CD measured by ¹H NMR analysiswas 99% or higher.

¹H NMR (CDCl₃) δ: 1.42-1.82 (m, 5H), 2.20-2.33 (m, 1H), 2.46 (t, J=2.2Hz, 1H), 2.56-2.72 (m, 2H), 3.04-3.24 (m, 2H), 3.35-3.50 (m, 1H), 3.91(dd, J=16.2, 2.4 Hz, 1H), 4.23 (dd, J=16.2, 2.2 Hz, 1H), 4.89-4.99 (m,2H), 5.48-5.50 (m, 1H), 5.69-5.82 (m, 1H), 7.43-7.59 (m, 3H), 8.14-8.18(m, 2H), 8.91 (d, J=4.1 Hz, 1H).

Synthesis of O-(2-butynyl)quinine (MeC≡CCH₂-Q)

Colorless viscous liquid O-(2-butynyl)quinine was synthesized (3.23 g,yield: 78%) in the same manner as that of the synthesis of Me-Q exceptthat methyl iodide was changed to 1-bromo-2-butyne. Chemical purity ofMeCH≡CCH₂-Q measured by ¹H NMR analysis was 99% or higher.

¹H NMR (CDCl₃) δ: 1.30-2.30 (m, 6H), 1.83 (s, 3H), 2.56-2.72 (m, 2H),3.04-3.24 (m, 2H), 3.35-3.60 (m, 1H), 3.87-3.95 (m, 1H), 3.95 (s, 3H),4.16 (dd, J=15.9, 2.4 Hz, 1H), 4.89-4.99 (m, 2H), 5.30-5.40 (m, 1H),5.69-5.80 (m, 1H), 7.36-7.43 (m, 3H), 8.03 (d, J=10.0, 1H), 8.75 (d,J=4.6 Hz, 1H).

Synthesis of O-(iso-propoxycarbonylmethyl)quinine (i-PRO₂CCH₂-Q)

Colorless viscous liquid O-(iso-propoxycarbonylmethyl)quinine wassynthesized (2.33 g, yield: 50%) in the same manner as that of thesynthesis of Me-Q except that methyl iodide was changed to iso-propylbromoacetate. Chemical purity of i-PrO₂CCH₂-Q measured by ¹H NMRanalysis was 99% or higher.

¹H NMR (CDCl₃) δ: 1.21 (d, J=1.9, 3H), 1.24 (d, J=1.6, 3H), 1.42-1.82(m, 5H), 2.20-2.40 (m, 1H), 2.56-2.72 (m, 2H), 3.04-3.24 (m, 2H),3.35-3.60 (m, 1H), 3.85 (d, J=16, 1H), 3.96 (s, 3H), 4.05 (d, J=16, 1H),4.90-5.00 (m, 2H), 5.02-5.10 (m, 1H), 5.20-5.35 (m, 1H), 5.69-5.82 (m,1H), 7.30-7.43 (m, 3H), 8.04 (d, J=9.7 Hz, 1H), 8.76 (d, J=4.6 Hz, 1H).

Synthesis of O-(o-methoxybenzyl)quinine (o-MeOC₆H₄CH₂-Q)

Colorless viscous liquid O-(o-methoxybenzyl)quinine was synthesized(3.56 g, yield: 73%) in the same manner as that of the synthesis of Me-Qexcept that methyl iodide was changed to o-methoxybenzyl bromide.Chemical purity of o-MeOC₆H₄CH₂-Q measured by ¹H NMR analysis was 99% orhigher.

¹H NMR (CDCl₃) δ: 1.42-1.82 (m, 5H), 2.20-2.40 (m, 1H), 2.56-2.72 (m,2H), 3.04-3.24 (m, 2H), 3.35-3.60 (m, 1H), 3.71 (s, 3H), 3.93 (s, 3H),4.48 (s, 2H), 4.88-4.97 (m, 2H), 5.2-5.3 (m, 1H), 5.69-5.82 (m, 1H),6.84 (d, J=8.4, 1H), 6.98 (t, J=7.6, 1H), 7.36-7.4 (m, 5H), 8.05 (d,J=9.7 Hz, 1H), 8.74 (d, J=4.6 Hz, 1H).

Synthesis of O-(o-chlorobenzyl)quinine (o-ClC₆H₄CH₂-Q)

Colorless viscous liquid O-(o-chlorobenzyl)quinine was synthesized (4.49g, yield: 91%) in the same manner as that of the synthesis of Me-Qexcept that methyl iodide was changed to o-chlorobenzyl chloride.Chemical purity of o-ClC₆H₄CH₂-Q measured by ¹H NMR analysis was 99% orhigher.

¹H NMR (CDCl₃) δ: 1.42-2.40 (m, 5H), 2.20-2.30 (m, 1H), 2.56-2.72 (m,2H), 3.04-3.24 (m, 2H), 3.35-3.60 (m, 1H), 3.95 (s, 3H), 4.48-4.59 (m,2H), 4.90-5.00 (m, 2H), 5.20-5.35 (m, 1H), 5.69-5.82 (m, 1H), 7.30-7.43(m, 7H), 8.06 (d, J=9.5 Hz, 1H), 8.76 (d, J=4.6 Hz, 1H).

Synthesis of O-(2-pyridinylmethyl)quinine (2-PyCH₂-Q)

Colorless viscous liquid O-(2-pyridinylmethyl)quinine was synthesized(3.65 g, yield: 80%) in the same manner as that of the synthesis of Me-Qexcept that methyl iodide was changed to 2-bromomethylpyridinehydrobromide. Chemical purity of 2-PyCH₂-Q measured by ¹H NMR analysiswas 99% or higher.

¹H NMR (CDCl₃) δ: 1.42-1.98 (m, 5H), 2.20-2.30 (m, 1H), 2.56-2.72 (m,2H), 3.04-3.24 (m, 2H), 3.35-3.50 (m, 1H), 3.94 (s, 3H), 4.57 (s, 2H),4.90-5.00 (m, 2H), 5.20-5.35 (m, 1H), 5.69-5.82 (m, 1H), 7.30-7.65 (m,5H), 7.73 (td, J=8.1, 1.6, 1H), 8.05 (d, J=9.5 Hz, 1H), 8.53 (d, J=4.6,1H), 8.74 (d, J=4.3 Hz, 1H).

Synthesis of O-(2-furylmethyl)quinine (2-FurCH₂-Q)

Colorless viscous liquid O-(2-furylmethyl)quinine was synthesized (0.44g, yield: 10%) in the same manner as that of the synthesis of Me-Qexcept that methyl iodide was changed to 2-furylmethyl mesylate.Chemical purity of 2-FurCH₂-Q measured by ¹H NMR analysis was 99% orhigher.

¹H NMR (CDCl₃) δ: 1.42-1.98 (m, 5H), 2.20-2.30 (m, 1H), 2.56-2.72 (m,2H), 3.04-3.24 (m, 2H), 3.35-3.50 (m, 1H), 3.93 (s, 3H), 4.29 (d, J=13Hz, 1H), 4.46 (d, J=13 Hz, 1H), 4.90-5.00 (m, 2H), 5.20-5.25 (m, 1H),5.69-5.82 (m, 1H), 6.22 (d, J=3.3 Hz, 1H), 6.31-6.32 (m, 1H), 7.30-7.49(m, 4H), 8.05 (d, J=9.5 Hz, 1H), 8.77 (d, J=4.6 Hz, 1H).

Synthesis of O-(2-thienylmethyl)quinine (2-ThCH₂-Q)

Pale yellow viscous liquid O-(2-thienylmethyl)quinine was synthesized(0.46 g, yield: 10%) in the same manner as that of the synthesis of Me-Qexcept that methyl iodide was changed to 2-thienylmethyl mesylate.Chemical purity of 2-ThCH₂-Q measured by ¹H NMR analysis was 99% orhigher.

¹H NMR (CDCl₃) δ: 1.42-1.98 (m, 5H), 2.20-2.30 (m, 1H), 2.56-2.72 (m,2H), 3.04-3.24 (m, 2H), 3.35-3.50 (m, 1H), 3.92 (s, 3H), 4.51 (d, J=12Hz, 1H), 4.65 (d, J=12 Hz, 1H), 4.90-5.00 (m, 2H), 5.20-5.25 (m, 1H),5.69-5.82 (m, 1H), 6.88 (d, J=3.0 Hz, 1H), 6.95-6.98 (m, 1H), 7.30-7.49(m, 4H), 8.05 (d, J=9.2 Hz, 1H), 8.78 (d, J=4.3 Hz, 1H).

Synthesis of O-(3-methyl-2-butenyl)quinine (Me₂C═CHCH₂-Q)

Pale yellow viscous liquid O-(3-methyl-2-butenyl)quinine was synthesized(2.80 g, yield: 65%) in the same manner as that of the synthesis of Me-Qexcept that methyl iodide was changed to 1-chloro-3-methyl-2-butene.Chemical purity of Me₂C═CHCH₂-Q measured by ¹H NMR analysis was 99% orhigher.

¹H NMR (CDCl₃) δ: 1.50 (s, 3H), 1.77 (s, 3H), 1.42-1.90 (m, 5H),2.20-2.30 (m, 1H), 2.56-2.72 (m, 2H), 3.04-3.24 (m, 2H), 3.35-3.50 (m,1H), 3.92-4.01 (m, 2H), 3.94 (s, 3H), 4.90-5.00 (m, 2H), 5.10-5.25 (m,1H), 5.34-5.39 (m, 1H), 5.69-5.82 (m, 1H), 7.30-7.43 (m, 3H), 8.04 (d,J=9.5 Hz, 1H), 8.75 (d, J=4.3 Hz, 1H).

Synthesis of O-aminocarbonylmethylquinine (NH₂COCH₂-Q)

Pale yellow viscous liquid O-aminocarbonylmethylquinine was synthesized(0.42 g, yield: 10%) in the same manner as that of the synthesis of Me-Qexcept that methyl iodide was changed to 2-bromoacetamide. Chemicalpurity of NH₂COCH₂-Q measured by ¹H NMR analysis was 99% or higher.

¹H NMR (CDCl₃) δ: 1.42-2.40 (m, 4H), 2.20-2.30 (m, 1H), 2.61-2.82 (m,3H), 3.04-3.14 (m, 1H), 3.20-3.41 (m, 2H), 3.88 (S, 2H), 3.94 (s, 3H),4.90-5.00 (m, 2H), 5.10-5.20 (m, 1H), 5.69-5.78 (m, 1H), 7.30-7.43 (m,3H), 8.06 (d, J=9.2 Hz, 1H), 8.76 (d, J=4.3 Hz, 1H).

Synthesis of O-(N,N-diethylaminocarbonylmethyl)quinine (Et₂NCO CH₂-Q)

Pale yellow viscous liquid O-(N,N-diethylaminocarbonylmethyl)quinine wassynthesized (4.61 g, yield: 96%) in the same manner as that of thesynthesis of Me-Q except that methyl iodide was changed to2-chloro-N,N-diethylacetamide. Chemical purity of Et₂NCOCH₂-Q measuredby ¹H NMR analysis was 99% or higher.

¹H NMR (CDCl₃) δ: 0.99 (t, J=7.3, 3H), 1.10 (t, J=6.8, 3H), 1.42-2.10(m, 6H), 2.20-2.30 (m, 1H), 2.61-2.82 (m, 2H), 3.07 (q, J=7.0 Hz, 2H),3.04-3.50 (m, 2H), 3.40 (q, J=7.0 Hz, 2H), 3.86-3.91 (m, 2H), 3.96 (s,3H), 4.90-5.00 (m, 2H), 5.10-5.30 (m, 1H), 5.73-5.86 (m, 1H), 7.36-7.45(m, 3H), 8.04 (d, J=9.2 Hz, 1H), 8.76 (d, J=4.3 Hz, 1H).

Synthesis of O-cyanomethylquinine (NCCH₂-Q)

Pale yellow viscous liquid O-cyanomethylquinine was synthesized (1.24 g,yield: 30%) in the same manner as that of the synthesis of Me-Q exceptthat methyl iodide was changed to chloroacetonitrile. Chemical purity ofNCCH₂-Q measured by ¹H NMR analysis was 99% or higher.

¹H NMR (CDCl₃) δ: 1.42-1.82 (m, 5H), 2.20-2.33 (m, 1H), 2.56-2.72 (m,2H), 3.04-3.24 (m, 1H), 3.35-3.50 (m, 2H), 3.96-3.98 (m, 1H), 3.96 (s,3H), 4.30 (d, J=16 Hz, 1H), 4.95-5.02 (m, 2H), 5.28-5.35 (m, 1H),5.69-5.82 (m, 1H), 7.26-7.43 (m, 3H), 8.06 (d, J=9.2 Hz, 1H), 8.78 (d,J=4.1 Hz, 1H).

Synthesis of O-cyclopropylmethylquinine (cyclo-C₃H₅CH₂-Q)

Colorless viscous liquid O-cyclopropylmethylquinine was synthesized(4.07 g, yield: 98%) in the same manner as that of the synthesis of Me-Qexcept that methyl iodide was changed to bromomethylcyclopropane.Chemical purity of cyclo-C₃H₅CH₂-Q measured by ¹H NMR analysis was 99%or higher.

¹H NMR (CDCl₃) δ: 0.12-0.18 (m, 2H), 0.49-0.53 (m, 2H), 1.42-2.40 (m,6H), 2.20-2.30 (m, 1H), 2.56-2.72 (m, 2H), 3.04-3.25 (m, 4H), 3.35-3.50(m, 1H), 3.94 (s, 3H), 4.90-5.00 (m, 2H), 5.00-5.23 (m, 1H), 5.69-5.82(m, 1H), 7.30-7.43 (m, 3H), 8.03 (d, J=9.2 Hz, 1H), 8.75 (d, J=4.3 Hz,1H).

Synthesis of O-(3-phenyl-2-propynyl)quinine (PhC≡CCH₂-Q)

Colorless viscous liquid O-(3-phenyl-2-propynyl)quinine was synthesized(3.23 g, yield: 78%) in the same manner as that of the synthesis of Me-Qexcept that methyl iodide was changed to 1-bromo-3-phenyl-2-propyne.Chemical purity of PhC≡CCH₂-Q measured by ¹H NMR analysis was 99% orhigher.

¹H NMR (CDCl₃) δ: 1.30-1.80 (m, 5H), 2.21-2.30 (m, 1H), 2.56-2.72 (m,2H), 3.04-3.24 (m, 2H), 3.35-3.60 (m, 1H), 3.89 (s, 3H), 4.15 (d, J=15.6Hz, 1H), 4.43 (d, J=15.6 Hz, 1H), 4.89-4.99 (m, 2H), 5.30-5.40 (m, 1H),5.69-5.80 (m, 1H), 7.26-7.36 (m, 7H), 7.48, (d, J=4.3 Hz, 1H), 8.04 (d,J=9.2 Hz, 1H), 8.77 (d, J=4.6 Hz, 1H).

Synthesis of O-(2-oxopropyl)quinine (MeCOCH₂-Q)

O-Propynylquinine (HC≡CCH₂-Q) (228 mg, 0.63 mmol) was dissolved in a 20%sulfuric acid (0.5 g) solution, mercury oxide (9.1 mg, 0.042 mmol) wasadded to the solution, and the mixture was stirred at room temperaturefor 10 minutes. The mixture was further stirred at 70° C. for two hoursand then cooled to 0° C., and a 2 N NaOH (3 ml) solution was addeddropwise to the reaction mixture carefully. The aqueous and organiclayers were separated, and the aqueous layer was extracted with ether(20 ml). The organic layer was combined with the extract, washed withwater (3 ml) and dried over magnesium sulfate. After filtration, thesolvent was evaporated under reduced pressure, and the residue waspurified by column chromatography (hexane:acetone:diethylamine=25:25:1)to give colorless viscous O-(2-oxopropyl)quinine (194 mg, yield: 81%).Chemical purity of MeCOCH₂-Q measured by ¹H NMR was 99% or higher.

¹H NMR (CDCl₃) δ: 1.40-1.82 (m, 5H), 2.17-2.33 (m, 1H), 2.19 (s, 3H),2.55-2.71 (m, 2H), 3.04-3.25 (m, 2H), 3.33-3.50 (m, 1H), 3.87-3.95 (m,1H), 3.93 (s, 3H), 4.22 (d, J=16.3 Hz, 1H), 4.89-4.98 (m, 2H), 5.31 (d,J=4.4 Hz, 1H), 5.70-5.82 (m, 1H), 7.36-7.43 (m, 3H), 8.04 (d, J=9.8 Hz,1H), 8.75 (d, J=4.6 Hz, 1H).

Synthesis of O-propynylquinidine (HC≡CCH₂-QD)

Colorless viscous liquid O-propynylquinidine was synthesized (2.47 g,yield: 62%) in the same manner as that of the synthesis of Me-QD exceptthat methyl iodide was changed to propynyl bromide. Chemical purity ofHC≡CCH₂-QD measured by ¹H NMR analysis was 99% or higher.

¹H NMR (CDCl₃) δ: 1.20-1.40 (m, 1H), 1.43-1.60 (m, 2H), 1.72-1.83 (m,1H), 2.00-2.13 (m, 1H), 2.18-2.34 (m, 1H), 2.46 (t, J=2.4 Hz, 1H),2.70-2.97 (m, 3H), 3.04-3.16 (m, 1H), 3.21-3.35 (m, 1H), 3.87-3.95 (m,1H), 3.93 (s, 3H), 4.24 (dd, J=16.0, 2.3 Hz, 1H), 5.05-5.16 (m, 2H),5.36 (d, J=4.0 Hz, 1H), 6.02-6.17 (m, 1H), 7.33-7.45 (m, 3H), 8.03 (d,J=9.8 Hz, 1H), 8.77 (d, J=4.5 Hz, 1H).

Synthesis of o-bisquininoxyxylene (o-Q-Xy-Q)

Pale yellow viscous liquid o-bisquininoxyxylene was synthesized (565 mg,yield: 15%) in the same manner as that of the synthesis of Me-Q exceptthat methyl iodide was changed to o-xylylene dichloride (875 mg, 5mmol). Chemical purity of o-Q-Xy-Q measured by ¹H NMR analysis was 99%or higher.

¹H NMR (CDCl₃) δ: 0.80-1.90 (m, 10H), 2.10-2.30 (m, 2H), 2.47-2.60 (m,4H), 2.93-3.28 (m, 6H), 3.88 (S, 6H), 4.36 (s, 4H), 4.87-4.95 (m, 4H),5.05 (brs, 2H), 5.61-5.75 (m, 2H), 7.27-7.48 (m, 10H), 8.04 (d, J=9.2Hz, 2H), 8.69 (d, J=4.1 Hz, 2H).

Synthesis of 1,4-bisquininoxybutane (Q-(CH₂)₄-Q)

Pale yellow viscous liquid 1,4-bisquininoxybutane was synthesized (0.35g, yield: 10%) in the same manner as that of the synthesis of Me-Qexcept that methyl iodide was changed to 1,4-butanediol bismesylate(1.23 g, 5 mmol). Chemical purity of Q-(CH₂)₄-Q measured by ¹H NMRanalysis was 99% or higher.

¹H NMR (CDCl₃) δ: 1.42-1.62 (m, 4H), 1.71-1.89 (m, 10H), 2.20-2.33 (m,2H), 2.56-2.72 (m, 4H), 3.04-3.24 (m, 4H), 3.31-3.52 (m, 6H), 3.94 (S,6H), 4.95-5.02 (m, 4H), 5.02-5.18 (m, 2H), 5.64-5.71 (m, 2H), 7.18-7.40(m, 6H), 8.03 (d, J=9.2 Hz, 2H), 8.74 (d, J=4.1 Hz, 2H).

Synthesis of 1,4-bisquininoxy-2-butyne (Q-CH₂C≡CCH₂-Q)

Pale yellow viscous liquid 1,4-bisquininoxy-2-butyne was synthesized(0.23 g, yield: 3%) in the same manner as that of the synthesis of Me-Qexcept that methyl iodide was changed to 2-butyne-1,4-diol bismesylate(1.21 g, 5 mmol). Chemical purity of Q-CH₂C≡CCH₂-Q measured by ¹H NMRanalysis was 99% or higher.

¹H NMR (CDCl₃) δ: 1.45-1.66 (m, 10H), 2.20-2.33 (m, 2H), 2.76-2.84 (m,4H), 3.10-3.29 (m, 6H), 3.96 (s, 6H), 4.10-4.80 (br, 4H), 4.94-5.05 (m,6H), 5.72-5.82 (m, 2H), 7.36-7.42 (m, 4H), 7.66 (d, J=2.7 Hz, 2H), 8.04(d, J=9.2 Hz, 2H), 8.74 (d, J=4.3 Hz, 2H).

Instrumental Analysis

Optical purity (enantiomer excess) was calculated according to thefollowing equation from each enantiomer ratio measured with an LC-6Atype high performance liquid chromatograph (HPLC) manufactured byShimazu Seisakusho, Ltd. and Chiralsel AS, OJ and OD columns (250×4.6mm) manufactured by Daicell Co., Ltd.

Enantiomer  excess  (ee, %) = {Absolute  value  of  [(enantiomer  R) − (enantiomer  S)]/[(enantiomer  R) + (enantiomer  S)]} × 100

Conversion (c) was measured with a GC-14A type gas-liquid chromatograph(GLC) manufactured by Shimazu Seisakusho, Ltd. and an HP-5 columnmanufactured by Hewlett-Packed Co., Ltd. in U.S.

s values, which are efficiency indexes of kinetic optical resolution,were calculated according to the following equation.

s = k(fast)/k(slow)   = ln [1 − c(1 + ee)]/ln [1 − c(1 − ee)](c=conversion, ee=enantiomer excess. Namely, enantiomer excess of oneoptically active nucleophile derivative (B) obtained by a reaction of asubstrate with a nucleophile, for example, an optically active aminoacid ester (R-2a) obtained in Example 1, corresponding esters obtainedin Examples 2 to 33 and Comparative Examples 1 to 9, an ester (S-5)obtained in Example 34 and Comparative Example 10 or an ester (S-8a)obtained in Example 35 and Comparative Example 11.)

The larger the s value, the higher is enantiomer selectivity.

Since Examples 36 and 37 and Comparative Example 12 are examples ofdynamic kinetic optical resolution, an s value of an obtained ester(S-8b) cannot be calculated. However, enantiomer selectivity can becompared by comparing optical purity of the ester (S-8b).

Chemical purity of recovered catalysts was calculated from proton ratiosof ¹H NMR of the recovered catalysts to impurities containing quinolinering moieties. ¹H NMR was measured with a GSX 270 type FT-NMR apparatusmanufactured by Japan Electron Optics Datum Co., Ltd.

EXAMPLE 1

Molecular sieve 4A (10 mg) was added to a solution ofN-allyloxycarbonyl-4-benzyl-1,3-oxazoline-2,5-dione (substrate (1)a;27.5 mg, 0.1 mmol) in anhydrous ether (4 ml) (concentration: 25 mmol/l)derived from phenylalanine, which is a racemic α-amino acid. The mixturewas cooled to −60° C., and Me-QD (13.5 mg, 0.4 equivalent) was added tothe mixture. After stirring for five minutes, a 5% anhydrousethanol/ether solution (50 μl; ethanol: 0.6 equivalent) was addedthereto slowly with a syringe. The reaction mixture was stirred at thistemperature for 30 hours, and then a 0.2 N aqueous hydrochloric acidsolution (5 ml) was added to the reaction mixture to stop the reaction.The temperature was raised to room temperature, the aqueous and organiclayers were separated, and the aqueous hydrochloric acid layer wasextracted with diethyl ether (2×2 ml). The combined organic layer wasdried over anhydrous sodium sulfate, and the extraction solvent wasevaporated under reduced pressure. A 20% water/tetrahydrofuran solution(5 ml) was added to the residue, followed by stirring at roomtemperature overnight. The resulting solution was concentrated, theresidue was dissolved in ether (3 ml), and the obtained solution wasextracted with a 1 N aqueous sodium carbonate solution (2×3 ml). Theorganic layer was washed with water (1 ml) and dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated to givean optically active amino acid ester, namely, an R configuration ester(R-2a) (144 mg, yield: 52%). Enantiomer excess of the amino acid estermeasured by HPLC analysis was 81% ee (s value=49).

The above-mentioned aqueous sodium carbonate layer was adjusted to pH 3with a 2 N aqueous hydrochloric acid solution, and extracted with ethylacetate (2×2 ml). The organic layer was dried over anhydrous sodiumsulfate, and the extraction solvent was evaporated under reducedpressure to give an optically active substance of the above-mentionedα-amino acid, namely, an S configuration amino acid (S-3a) (90 mg,yield: 36%). Enantiomer excess of the amino acid measured by HPLCanalysis was 99% ee.

The reactions in this Example are illustrated by the following formula(1).

In order to recover the catalyst, the combined aqueous hydrochloric acidlayer was adjusted to pH 10 with a 1 N aqueous sodium hydroxidesolution, and extracted with ethyl acetate (2×2 ml). The organic layerwas dried over anhydrous sodium sulfate, and the extraction solvent wasevaporated under reduced pressure to give Me-QD (12.7 mg, recovery:94%). Chemical purity of recovered Me-QD was 99% or higher according to¹H NMR analysis.

Tables 1 and 2 show the reagents, the reaction conditions, the reactionresults and the like in Example 1.

COMPARATIVE EXAMPLE 1

An experiment was performed in the same manner as in Example 1 exceptthat the catalyst, the reaction conditions and the like were changed asshown in Table 1 to give results shown in Table 2.

EXAMPLES 2 TO 33 AND COMPARATIVE EXAMPLES 2 TO 9

Experiments were performed in the same manner as in Example 1 exceptthat the reagents, the reaction conditions and the like were changed asshown in Table 1 to give results shown in Table 2.

In Table 1, the substrates are the above-mentioned substrates (1)a,(1)b, (1)c and (1)d. In Table 2, the esters are S configuration esters(S-2a, S-2b, S-2c and S-2d) corresponding to the R configuration ester(R-2a) in Example 1, and the amino acids are R configuration amino acids(R-3a, R-3b, R-3c and R-3d) corresponding to the S configuration aminoacid (S-3a) in Example 1.

EXAMPLE 34

An experiment was performed in the same manner as in Example 1 exceptthat the reagents, the reaction conditions and the like were changed asshown in Table 1 to give results shown in Table 2.

The reaction in this Example is represented by the formula (2).

COMPARATIVE EXAMPLE 10

An experiment was performed in the same manner as in Example 34 exceptthat the catalyst, the reaction conditions and the like were changed asshown in Table 1 to give results shown in Table 2.

EXAMPLE 35

An experiment was performed in the same manner as in Example 1 exceptthat the reagents, the reaction conditions and the like were changed asshown in Table 1 to give results shown in Table 2.

The reaction in this Example is represented by the formula (3).

COMPARATIVE EXAMPLE 11

An experiment was performed in the same manner as in Example 35 exceptthat the catalyst, the reaction conditions and the like were changed asshown in Table 1 to give results shown in Table 2.

EXAMPLE 36

An experiment was performed in the same manner as in Example 1 exceptthat the reagents, the reaction conditions and the like were changed asshown in Table 1 to give results shown in Table 2 by dynamic kineticoptical resolution.

The reaction in this Example is represented by the formula (4).

EXAMPLE 37 AND COMPARATIVE EXAMPLE 12

Experiments were performed in the same manner as in Example 36 exceptthat the catalyst, the reaction conditions and the like were changed asshown in Table 1 to give results shown in Table 2.

TABLE 1 Reac- Substrate Reac- tion Concen- tion temper- Sub- trationCatalyst Nucleophile time ature strate Solvent [mmol/l] (equivalent)(equivalent) [hr] [° C.] Example 1 (1)a Et₂O 25 Me-QD(0.4) EtOH(0.6) 30−60 Example 2 (1)a Et₂O 25 Me-Q(0.4) EtOH(0.6) 30 −60 Example 3 (1)aEt₂O 25 Bn-Q(04) EtOH(0.6) 34 −60 Example 4 (1)a Et₂O 25CH₂═CHCH₂-Q(0.4) EtOH(0.6) 40 −60 Example 5 (1)a Et₂O 25 Et-Q(0.4)EtOH(0.6) 33 −60 Example 6 (1)a Et₂O 25 CH≡CCH₂-Q(0.4) EtOH(0.6) 30 −60Example 7 (1)a Et₂O 25 ^(t)BuO₂CCH₂-Q(0.4) EtOH(0.6) 33 −60 Example 8(1)a Et₂O 25 MeOCH₂CH₂-Q(0.4) EtOH(0.6) 37 −60 Example 9 (1)a Toluene 25Me-Q(0.4) EtOH(0.6) 20 −60 Example 10 (1)a Toluene 125 Me-Q(0.4)EtOH(0.6) 24 −60 Example 11 (1)a Et₂O 125 Me-Q(0.4) EtOH(0.6) 34 −60Example 12 (1)b Et₂O 25 ^(t)BuO₂CCH₂-Q(0.4) MeOH(0.6) 27 −60 Example 13(1)c Et₂O 25 ^(t)BuO₂CCH₂-Q(0.4) CH₂═CHCH₂OH(0.6) 25 −78 Example 14 (1)dEt₂O 25 ^(t)BuO₂CCH₂-Q(0.4) CF₃CH₂OH(0.6) 41 −60 Example 15 (1)a Et₂O 25HC≡CCH₂-HQ(0.4) EtOH(0.6) 35 −60 Example 16 (1)a Et₂O 25 HC≡CCH₂-CD(0.4)EtOH(0.6) 30 −60 Example 17 (1)a Et₂O 25 MeC≡CCH₂-Q(0.4) EtOH(0.6) 37−60 Example 18 (1)a Et₂O 25 ^(i)PrO₂CCH₂-Q(0.4) EtOH(0.6) 30 −60 Example19 (1)a Et₂O 25 o-MeOC₆H₄CH₂-Q(0.4) EtOH(0.6) 27 −60 Example 20 (1)aEt₂O 25 o-ClC₆H₄CH₂-Q(0.4) EtOH(0.6) 30 −60 Example 21 (1)a Et₂O 252-PyCH₂-Q(0.4) EtOH(0.6) 29 −60 Example 22 (1)a Et₂O 25 2-FurCH₂-Q(0.4)EtOH(0.6) 37 −60 Example 23 (1)a Et₂O 25 2-ThCH₂-Q(0.4) EtOH(0.6) 30 −60Example 24 (1)a Et₂O 25 Me₂C═CHCH₂-Q(0.4) EtOH(0.6) 30 −60 Example 25(1)a Et₂O 25 H₂NCOCH₂-Q(0.4) EtOH(0.6) 31 −60 Example 26 (1)a Et₂O 25Et₂NCOCH₂-Q(0.4) EtOH(0.6) 27 −60 Example 27 (1)a Et₂O 25 NCCH₂-Q(0.4)EtOH(0.6) 33 −60 Example 28 (1)a Et₂O 25 cyclo-C₃H₅CH₂-Q(0.4) EtOH(0.6)33 −60 Example 29 (1)a Et₂O 25 PhC≡CCH₂-Q(0.4) EtOH(0.6) 30 −60 Example30 (1)a Et₂O 25 MeCOCH₂-Q(0.4) EtOH(0.6) 28 −60 Example 31 (1)a Et₂O 25o-Q-Xy-Q(0.2) EtOH(0.6) 30 −60 Example 32 (1)a Et₂O 25 Q-(CH₂)₄-Q(0.2)EtOH(0.6) 28 −60 Example 33 (1)a Toluene 125 HC≡CCH₂-QD(0.4) EtOH(0.6)31 −60 Example 34  4 Et₂O 25 ^(t)BuO₂CCH₂-Q(0.4) EtOH(0.6) 30 −60Example 35 (7)a Et₂O 25 ^(t)BuO₂CCH₂-Q(0.2) CH₂═CHCH₂OH(1.0) 20 −78Example 36 (7)b Et₂O 25 ^(t)BuO₂CCH₂-Q(0.2) CH₂═CHCH₂OH(1.2) 23 −78Example 37 (7)b Et₂O 25 Q-CH₂C≡CH₂-Q(0.2) CH₂═CHCH₂OH(1.2) 27 −60Comparative (1)a Et₂O 25 QD(0.4) EtOH(0.6) 28 −60 Example 1 Comparative(1)a Et₂O 25 Q(0.4) EtOH(0.6) 29 −60 Example 2 Comparative (1)b Et₂O 25Q(0.4) MeOH(0.6) 35 −60 Example 3 Comparative (1)c Et₂O 25 Q(0.4)CH₂═CHCH₂OH(0.6) 30 −78 Example 4 Comparative (1)d Et₂O 25 Q(0.4)CF₃CH₂OH(0.6) 43 −60 Example 5 Comparative (1)a Et₂O 25 HQ(0.4)EtOH(0.6) 29 −60 Example 6 Comparative (1)a Et₂O 25 CD(0.4) EtOH(0.6) 36−60 Example 7 Comparative (1)a Toluene 125 QD(0.4) EtOH(0.6) 29 −60Example 8 Comparative (1)a Toluene 125 (DHQD)₂AQN(0.2) EtOH(0.6) 33 −60Example 9 Comparative  4 Et₂O 25 Q(0.4) EtOH(0.6) 39 −60 Example 10Comparative (7)a Et₂O 25 Q(0.2) CH₂═CHCH₂OH(1.0) 27 −78 Example 11Comparative (7)b Et₂O 25 Q(0.2) CH₂═CHCH₂OH(1.2) 24 −78 Example 12

TABLE 2 Catalyst Purity Conver- Ester Amino acid Purity after sion ee %s ee % before Recovery recovery (%) (yield %) value (yield %) use (%)(%) (%) Example 1 55 R-2a 81(52) 49 S-3a 99(36) >99 94 >99 Example 2 51S-2a 87(46) 45 R-3a 91(42) >99 92 >99 Example 3 55 S-2a 78(49) 30 R-3a96(38) >99 95 >99 Example 4 54 S-2a 83(47) 46 R-3a 97(38) >99 96 >99Example 5 56 S-2a 77(47) 34 R-3a 98(37) >99 94 >99 Example 6 53 S-2a85(47) 48 R-3a 97(38) >99 94 >99 Example 7 54 S-2a 84(46) 56 R-3a99(38) >99 91 >99 Example 8 53 S-2a 82(46) 33 R-3a 93(37) >99 96 >99Example 9 54 S-2a 81(49) 35 R-3a 95(37) >99 97 >99 Example 10 55 S-2a76(48) 24 R-3a 93(38) >99 96 >99 Example 11 58 S-2a 65(47) 14 R-3a90(36) >99 96 >99 Example 12 54 S-2b 84(48) 56 R-3b 99(38) >99 90 >99Example 13 52 S-2c 88(46) 59 R-3c 96(36) >99 91 >99 Example 14 53 S-2d86(46) 55 R-3d 96(36) >99 92 >99 Example 15 52 S-2a 86(48) 45 R-3a94(40) >99 94 >99 Example 16 58 S-2a 70(50) 22 R-3a 98(38) >99 94 >99Example 17 51 S-2a 86(45) 40 R-3a 90(40) >99 95 >99 Example 18 52 S-2a86(47) 45 R-3a 95(39) >99 93 >99 Example 19 55 S-2a 79(47) 34 R-3a94(37) >99 94 >99 Example 20 55 S-2a 78(47) 30 R-3a 94(38) >99 96 >99Example 21 57 S-2a 74(48) 30 R-3a 99(38) >99 96 >99 Example 22 58 S-2a72(51) 34 R-3a 99(34) >99 96 >99 Example 23 57 S-2a 75(49) 39 R-3a99(34) >99 94 >99 Example 24 57 S-2a 75(48) 39 R-3a 99(33) >99 95 >99Example 25 56 S-2a 78(50) 44 R-3a 99(36) >99 96 >99 Example 26 56 S-2a76(48) 29 R-3a 98(35) >99 92 >99 Example 27 53 S-2a 84(46) 42 R-3a96(40) >99 91 >99 Example 28 57 S-2a 74(48) 30 R-3a 98(36) >99 95 >99Example 29 53 S-2a 84(47) 42 R-3a 95(44) >99 94 >99 Example 30 52 S-2a85(46) 40 R-3a 92(38) >99 92 >99 Example 31 57 S-2a 74(51) 30 R-3a99(35) >99 94 >99 Example 32 58 S-2a 72(48) 34 R-3a 98(35) >99 98 >99Example 33 55 R-2a 80(47) 40 S-3a 99(38) >99 96 >99 Example 34 54 S-5 82(47) 40 R-6  97(38) >99 90 >99 Example 35 52 S-8a 88(46) 59 R-9a97(35) >99 92 >99 Example 36 100 S-8b 90(70) — — — >99 91 >99 Example 37100 S-8b 95(70) — — — >99 95 >99 Comparative 57 R-2a 74(48) 30 S-3a98(38) >99 98 95 Example 1 Comparative 56 S-2a 71(47) 18 R-3a 91(36) >9998 96 Example 2 Comparative 58 S-2b 65(54) 14 R-3b 91(32) >99 97 93Example 3 Comparative 59 S-2c 61(52) 11 R-3c 89(33) >99 95 93 Example 4Comparative 58 S-2d 63(53) 12 R-3d 88(31) >99 97 95 Example 5Comparative 56 S-2a 70(49) 17 R-3a 90(33) >99 95 91 Example 6Comparative 42 S-2a 60(37)  6 R-3a 43(42) >99 96 91 Example 7Comparative 57 R-2a 63(50) 11 S-3a 85(32) >99 97 93 Example 8Comparative 57 R-2a 72(48) 23 S-3a 97(34) >99 95 >99 Example 9Comparative 60 S-5  56(55)  9 R-6  84(32) >99 94 97 Example 10Comparative 58 S-8a 69(55) 20 R-9a 96(33) >99 96 94 Example 11Comparative 100 S-8b 68(65) — — — >99 93 95 Example 12 R and S mean an Rconfiguration and an S configuration respectively.

As shown by the above-mentioned table, higher enantiomer selectivity (svalues) was obtained in Examples 1 to 8 and 12 to 35 compared withComparative Examples 1 to 7, 10 and 11. Examples 36 and 37 are exampleswherein dynamic kinetic optical resolution was performed, and higherenantiomer selectivity (optical purity) was obtained compared withComparative Example 12. Examples 9 and 10 are examples wherein toluenewas used as the solvent, and the substrate concentration in the latterwas five times higher than that in the former. Examples 2 and 11 areexamples wherein ethyl ether was used as the solvent, and the substrateconcentration in the latter was five times higher than that in theformer. When the substrate concentration is increased, the s valuegenerally is lowered. However, when aromatic solvents such as toluenewere used, the lowering in s value was smaller than those in the case ofother solvents. Example 33 is an example wherein the reaction wasperformed in the high substrate concentration using toluene as thesolvent, and higher enantiomer selectivity (s value) was obtainedcompared with Comparative Examples 8 and 9.

Higher purity after recovering the catalysts were obtained in Examplescompared with Comparative Examples.

INDUSTRIAL APPLICABILITY

Efficient kinetic optical resolution of recemic carboxylic acidderivatives can be performed, particularly, enantiomer selectivity (svalues) is improved, and catalysts can be recovered in high purity bythe present invention.

1. An optically active compound represented by the following generalformula (C) or (D),

wherein R¹ is a group having one to 20 carbon atoms and represented bythe following general formula (G), (H), or (J),

wherein R⁴, R⁶, R⁷, R⁸ and R⁹, the same or different, are a hydrogenatom or a substituted or unsubstituted, saturated or unsaturated,straight-chain, branched or alicyclic aliphatic hydrocarbon group whichcan have an oxygen atom, or a substituted or unsubstituted aromatichydrocarbon group, R² is ethyl or vinyl, and R⁵ is a hydrogen atom ormethoxy.
 2. An optically active compound represented by the followinggeneral formula (C) or (D),

wherein R¹ is allyl, propynyl, tert-butoxycarbonylmethyl,2-methoxyethyl, 2-butynyl, iso-propoxycarbonylmethyl,methoxycarbonylniethyl, o-methoxybenzyl, m-methoxybenzyl,p-methoxybenzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl,1-naphthylmethyl, 2-naphthylmethyl, prenyl, cinnamyl, methallyl,homoallyl, homobenzyl, N,N-diethylaminocarbonylmethyl, cyanomethyl,acetylmethyl, cyclopropylmethyl, 3-phenyl-2-propynyl,3-methoxycarbonyl-2-propynyl or 3-methoxycarbonyl-2-propenyl, R² isethyl or vinyl, and R⁵ is a hydrogen atom or methoxy.
 3. An opticallyactive compound according to claim 1, wherein R⁴, R⁶, R⁷, R⁸, and R⁹,the same or different, are a hydrogen atom or a saturated or unsaturatedhydrocarbon group which can have an oxygen atom, or an aromatichydrocarbon group.